CONTACT

Patrick MEHLEN
patrick.mehlen
@lyon.unicancer.fr


+33 (0)4 78 78 28 70

Cheney A - 3rd floor
Centre Léon Bérard
28 rue Laennec
69 373 LYON Cedex 08
France
ARRIGO Patrick

Professeur des universités UCBL1
patrick.arrigo@lyon.unicancer.fr

BERNET Agnès
Professeur des Universités UCBL1
agnes.bernet@lyon.unicancer.fr
BISSARDON Bérangère
Secrétaire-gestionnaire CNRS
berangere.bissardon@lyon.unicancer.fr
BLACHIER Jonathan
BOSCH Sylvie

Adjoint technique CNRS
sylvie.bosch@lyon.unicancer.fr

BROUTIER Laura
CASSIER Philippe
CASTETS Marie
CHAIX Yohann
Chargé d'affaires
yohann.chaix@lip-lyon1.fr
CORSET Véronique
COSTECHAREYRE Clélia
CREVEAUX Marion
DANTE Robert
DELCROS Jean-Guy
DEVAILLY Guillaume
DUCAROUGE Benjamin
Chercheur post-doctorant
benjamin.ducarouge@lyon.unicancer.fr
FAVROT Clémentine
FOMBONNE Joanna
Maitre de conférences des Universités UCBL1
joanna.fombonne@lyon.unicancer.fr
GIBERT Benjamin
Chercheur post-doctorant
benjamin.gibert@lyon.unicancer.fr
GODDARD Isabelle
Ingénieur de recherche CNRS
isabelle.goddard@lyon.unicancer.fr
GOLDSCHNEIDER David
Chercheur post-doctorant
david.goldschneider@lyon.unicancer.fr
GRANDIN Mélodie
GRATADOU Lise
GUIX Catherine
LAMBERT Sophie
LE GUERNEVEL Solène
LIN Shuseng
MATHOT Pauline
MEHLEN Patrick
Chef d'équipe, DR1 CNRS
patrick.mehlen@lyon.unicancer.fr
MENARD Marie
MEURETTE Olivier
Maitre de conférences des Universités UCBL1
olivier.meurette@lyon.unicancer.fr
NEGULESCU Ana
OZMADENCI Duygu
PARADISI Andrea
VIAL Jonathan
VIEUGUE Pauline
WANG Hong
Voir les objectifs et projets Voir les publications

OBJECTIVES

The team originally proposed the dependence receptor theory. These receptors have a dual signaling ability : when bound to their ligand they induce survival pathways, whereas they induce an active signal of cell death in the absence of their ligand. The team currently works on three approaches: (1) deciphering the molecular mechanisms of dependence receptor-induced cell death; (2) characterizing new dependence receptors; (3) analizing the physiological role of these receptors in the development of vascular and nervous systems as well as in tumor progression. Finally, the team aims at transforming basic knowlegde into therapeutic approaches to restore cell death induced by these receptors in tumors.

PROJECT

Our team investigates all aspects related to dependence receptors (DR). These receptors have a dual signaling ability: in the presence of their cognate ligand they induce a survival signal, whereas they transduce an active apoptotic signal in the absence of such ligands. More than twenty such receptors have been described to date and we speculated that their activity is instrumental for embryonic development as well as for the regulation of tumorigenesis (Mehlen et al., 2011, Nat Rev Cancer).

This concept of dependence receptors arose by highlighting the importance of such receptors in developmental processes and in tumor development. We initially proposed that the dependence receptor function was important to regulate migration and localization of cells during development (for example neurons and endothelial cells) (Thibert et al., 2003, Science; Mille et al., 2009, Nature Cell Biology; Castets et al., 2009, Dev Cell). We also showed that they had a tumor suppressive function by limiting tumor cell development in the absence of their ligands (Mazelin et al., 2004, Nature; Castets et al., 2012, Nature). Beyond the fact that the loss of receptors can lead to tumor progression, we have also shown that tumoral escape can be achieved through autocrine secretion of the ligand by cancer cells (Fitamant et al., 2008, PNAS). This observation led us to propose a therapeutic strategy based on inhibiting the binding of ligands, thus restoring the pro-apoptotic function of dependence receptors (Delloye-Bourgeois et al., 2009a, JEM; Delloye-Bourgeois et al., 2009b, JNCI; Bouzas-Rodriguez et al., 2010, JCI). 

Three complementary approaches are now being undertaken within the team: first, the identification of the molecular mechanisms leading to DR-induced cell death; second, the identification of novel dependence receptors and study of their relevance in tumour progression and development; third a “from the bench to the clinic” approach, in close collaboration with Netris Pharma to develop interfering agents to restore death of cancer cells in patients. This close collaboration has led to the entry into Phase I clinical trials of a drug candidate at the beginning of 2017, trial supported by the Léon Berard Centre. 

PUBLICATIONS

2013

Delcros JG, Mehlen P.Dependence receptors: life or death choices. (2013) Bull Cancer. Dec;100(12):1261-74

Paradisi A, Creveaux M, Gibert B, Devailly G, Redoulez E, Neves D, Cleyssac E, Treilleux I, Klein C, Niederfellner G, Cassier PA, Bernet A, Mehlen P.  Combining chemotherapeutic agents and netrin-1 interference potentiates cancer cell death. (2013) EMBO Mol Med. Dec;5(12):1821-34.

Semaphorin 3E Suppresses Tumor Cell Death Triggered by the Plexin D1 Dependence Receptor in Metastatic Breast Cancers. Luchino J, Hocine M, Amoureux MC, Gibert B, Bernet A, Royet A, Treilleux I, Lécine P, Borg JP, Mehlen P, Chauvet S, Mann F. Cancer Cell. 2013 Nov 11;24(5):673-85

Caspase-generated fragment of the Met receptor favors apoptosis via the intrinsic pathway independently of its tyrosine kinase activity. Lefebvre J, Muharram G, Leroy C, Kherrouche Z, Montagne R, Ichim G, Tauszig-Delamasure S, Chotteau-Lelievre A, Brenner C, Mehlen P, Tulasne D. (2013) Cell Death Dis. Oct 17;4:e871

The Dependence Receptor TrkC Triggers Mitochondria-Dependent Apoptosis upon Cobra-1 Recruitment. Ichim G, Genevois AL, Ménard M, Yu LY, Coelho-Aguiar JM, Llambi F, Jarrosson-Wuilleme L, Lefebvre J, Tulasne D, Dupin E, Le Douarin N, Arumäe U, Tauszig-Delamasure S, Mehlen P. (2013) Mol Cell. Sep 12;51(5):632-46.

Sonic Hedgehog promotes tumor cell survival by inhibiting CDON pro-apoptotic activity. Delloye-Bourgeois C, Gibert B, Rama N, Delcros JG, Gadot N, Scoazec JY, Krauss R, Bernet A, Mehlen P. (2013) PLoS Biol.  Aug;11(8):e1001623.

Analysis of the dominant effects mediated by wild type or R120G mutant of αB-crystallin (HspB5) towards Hsp27 (HspB1). Simon S, Dimitrova V, Gibert B, Virot S, Mounier N, Nivon M, Kretz-Remy C, Corset V, Mehlen P, Arrigo AP. (2013) PLoS One. Aug 12; 8(8):e70545

Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression. Zhu Y, Li Y, Haraguchi S, Yu M, Ohira M, Ozaki T, Nakagawa A, Ushijima T, Isogai E, Koseki H, Nakamura Y, Kong C, Mehlen P, Arakawa H, Nakagawara A. (2013) J Clin Invest.  Jul 1;123(7):2935-47

Dependence receptor TrkC is a putative colon cancer tumor suppressor. Genevois AL, Ichim G, Coissieux MM, Lambert MP, Lavial F, Goldschneider D, Jarrosson-Wuilleme L, Lepinasse F, Gouysse G, Herceg Z, Scoazec JY, Tauszig-Delamasure S, Mehlen P. (2013) Proc Natl Acad Sci U S A.  Feb 19;110(8):3017-22.
 

2012

Dupre A, Paradisi A, Langonnet S, Gandini A, Mehlen P, Rivoire M. Bevacizumab impairs hepatocyte proliferation after partial hepatectomy in a rabbit model. (2012) Anticancer Res. Dec;32(12):5193-200.

Rama N, Goldschneider D, Corset V, Lambert J, Pays L, Mehlen P. Amyloid precursor protein regulates netrin-1-mediated commissural axon outgrowth. (2012) J Biol Chem. Aug 24;287(35):30014-23.

Delloye-Bourgeois C, Goldschneider D, Paradisi A, Therizols G, Belin S, Hacot S, Rosa-Calatrava M, Scoazec JY, Diaz JJ, Bernet A, Mehlen P.  Nucleolar localization of a netrin-1 isoform enhances tumor cell proliferation. (2012) Sci Signal. Aug 7;5(236):ra57.

Gibert B, Eckel B, Gonin V, Goldschneider D, Fombonne J, Deux B, Mehlen P, Arrigo AP, Clézardin P, Diaz-Latoud C. Targeting heat shock protein 27 (HspB1) interferes with bone metastasis and tumour formation in vivo. (2012) Br J Cancer. Jun 26;107(1):63-70.

Ichim G, Tauszig-Delamasure S, Mehlen P.Neurotrophins and cell death. Exp Cell Res. Jul 1;318(11):1221-8.
Broutier L, Castets M. (2012) DCC, come back of a suppressor gene in colorectal cancer (2012) Med Sci (Paris). May;28(5):465-8. 

Lambert E, Coissieux MM, Laudet V, Mehlen P. Netrin-4 acts as a pro-angiogenic factor during zebrafish development. (2012) J Biol Chem. Feb 3;287(6):3987-99.

2011
DCC constrains tumour progression via its dependence receptor activity. Castets M, Broutier L, Molin Y, Brevet M, Chazot G, Gadot N, Paquet A, Mazelin L, Jarrosson-Wuilleme L, Scoazec JY, Bernet A, Mehlen P. (2011) Nature. Dec 11;482(7386):534-7.

Variants in the netrin-1 receptor UNC5C prevent apoptosis and increase risk of familial colorectal cancer. Coissieux MM, Tomsic J, Castets M, Hampel H, Tuupanen S, Andrieu N, Comeras I, Drouet Y, Lasset C, Liyanarachchi S, Mazelin L, Puisieux A, Saurin JC, Scoazec JY, Wang Q, Aaltonen L, Tanner SM, de la Chapelle A, Bernet A, Mehlen P. (2011) Gastroenterology. Dec;141(6):2039-46.

Rajasundari A, Pays L, Mehlen P, Ramesh G.  Netrin-1 overexpression in kidney proximal tubular epithelium ameliorates cisplatin nephrotoxicity. (2011) Lab Invest. Dec;91(12):1717-26.

Cabrera JR, Bouzas-Rodriguez J, Tauszig-Delamasure S, Mehlen P.  RET modulates cell adhesion via its cleavage by caspase in sympathetic neurons. (2011) J Biol Chem. Apr 22;286(16):14628-38.

Mehlen P, Delloye-Bourgeois C, Chédotal A.  Novel roles for Slits and netrins: axon guidance cues as anticancer targets? (2011) Nat Rev Cancer. Mar;11(3):188-97.

Mehlen P, Bredesen DE.  Dependence receptors: from basic research to drug development. (2011) Sci Signal. Jan 25;4(157):mr2.

2010

Mehlen P. Dependence receptors: the trophic theory revisited. (2010) Sci Signal. Dec 7;3(151):pe47.

Guenebeaud C, Goldschneider D, Castets M, Guix C, Chazot G, Delloye-Bourgeois C, Eisenberg-Lerner A, Shohat G, Zhang M, Laudet V, Kimchi A, Bernet A, Mehlen P. The dependence receptor UNC5H2/B triggers apoptosis via PP2A-mediated dephosphorylation of DAP kinase. (2010) Mol Cell. Dec 22;40(6):863-76.

Thibert C, Fombonne J. Dependence receptors: mechanisms of an announced death. (2010) Cell Cycle. Jun 1;9(11):2085-91

Goldschneider D, Mehlen P. (2010) Dependence receptors: a new paradigm in cell signaling and cancer therapy. Oncogene. Apr 1;29(13):1865-82.

Paradisi A, Mehlen P. Netrin-1, a missing link between chronic inflammation and tumor progression. (2010)Cell Cycle. Apr 1;9(7):1253-62.

Castets M, Mehlen P. Netrin-1 role in angiogenesis: to be or not to be a pro-angiogenic factor? (2010) Cell Cycle. Apr 15;9(8):1466-71.

Bouzas-Rodriguez J, Cabrera JR, Delloye-Bourgeois C, Ichim G, Delcros JG, Raquin MA, Rousseau R, Combaret V, Bénard J, Tauszig-Delamasure S, Mehlen P. Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis. (2010) J Clin Invest. Mar;120(3):850-8.

2009

Paradisi A, Maisse C, Coissieux MM, Gadot N, Lépinasse F, Delloye-Bourgeois C, Delcros JG, Svrcek M, Neufert C, Fléjou JF, Scoazec JY & P. Mehlen. Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal cancer progression. (2009) Proc. Natl. Acad. Sci. USA Oct. 6; 106, 17146-51.

Mille F, Thibert C, Fombonne J, Rama N, Guix C, Hayashi H, Corset V, Reed JC & P. Mehlen. The Patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex. (2009). Nature Cell Biology.Jun; 11 (6), 739-46.

Lourenço FC, Galvan V, Fombonne J, Corset V, Llambi F, Müller U, Bredesen DE, Mehlen P. Netrin-1 interacts with amyloid precursor protein and regulates amyloid-beta production. (2009) Cell Death Differ.May;16(5):655-63

Delloye-Bourgeois C, Fitamant J, Paradisi A, Cappellen D, Douc-Rasy S, Raquin M.A, Stupack D, Nakagawara A, Combaret V, Puisieux A, Couanet-Valteau D, Bénard J, Bernet A & Mehlen P. Netrin-1 acts as a survival factor for aggressive neuroblastoma. (2009b) J. Exp. Medicine Apr 13; 206, 833-847.

Castets M, Coissieux MM, Delloye-Bourgeois C, Bernard L, Delcros JG, Bernet A, Laudet V & P. Mehlen.Inhibition of endothelial cell apoptosis by netrin-1 during angiogenesis.  (2009). Dev. Cell. Apr; 16, 614-620.

Fombonne J, Rabizadeh S, Banwait S, Mehlen P, Bredesen DE. Selective vulnerability in Alzheimer's disease: amyloid precursor protein and p75(NTR) interaction. (2009) Ann Neurol. Mar;65(3):294-303


2008
Fitamant J, Guenebeaud C, Coissieux MM, Guix C, Treilleux I, Scoazec JY, Bachelot T, Bernet A, Mehlen P. Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer (2008).Proc Natl Acad Sci U S A. Mar 25;105(12):4850-5. 

Paradisi A.*, Maisse C.*, Bernet A., Coissieux MM., Maccarrone M., Scoazec JY., Mehlen P. (*equaly contributed). NF-κB regulates netrin-1 expression and affects the conditional tumor suppressive activity of the netrin-1 receptors (2008). Gastroenterology 2008 135(4):1248-57 

Bernet A, Fitamant J. Netrin-1 and its receptors in tumour growth promotion (2008). Expert Opin Ther Targets. Aug;12(8):995-1007. 

2004-2007
Bernet A, Mazelin L, Coissieux MM, Gadot N, Ackerman SL, Scoazec JY, Mehlen P. Inactivation of the UNC5C Netrin-1 receptor is associated with tumor progression in colorectal malignancies (2007).Gastroenterology. Dec;133(6):1840-8. Aug 2 

Bernet A and Mehlen P. Dependence receptors: when apoptosis controls tumor progression (2007). Bull Cancer. Apr 1;94(4):E12-7. 

Mehlen P and Bernet A. Netrin Pipes up (2005). Nature Cell Biology, 7 (11),1052-3 

Bernet A and Mehlen P. Netrin-1 and its dependence receptors : function in colorectal tumorigenesis. (2005)Pathol.Biol. 53 (6). 328-333. 

Mazelin L, Bernet A, Bidaud-Bonod C, Pays L, Gespach C, Bredesen DE, Scoazec JY and Mehlen P. Netrin-1 controls colorectal tumorigenesis by regulating apoptosis (2004). Nature Sep 2 ; 431(7004), 80-84


Principaux financements
INSERM
CNRS
Université Claude Bernard Lyon I
Institut National du Cancer (INCa)
Association pour la Recherche sur le Cancer (ARC)
Ligue Nationale contre le Cancer (Comités de l’Ain, de l’Ardèche, de la Drôme, du Puy de Dôme, du Rhône, de Savoie et de Saône et Loire)
Agence Nationale pour la Recherche (ANR)
Lyon Biopole
Laboratoire d'Excellence (LabEx) DevWeCan (Grand Emprunt)
Fondation pour la Recherche Médicale (FRM) 

Principales collaborations nationales
Institut Gustave Roussy (Villejuif) / Laurence ZITVOGEL
INSERM U851 (Lyon) / Jacqueline MARVEL et Thierry WALZER
Institut de Recherche Thérapeutique IRT UN Unité INSERM 892, Centre de Recherche en Cancérologie Nantes-Angers (Nantes) / Henri VIE
Institut Curie (Paris) / Sebastian AMIGORENA, Vassili SOUMELIS, …
Université Pierre et Marie Curie (Paris) / Benoit SALOMON et Gilles MARODON
INSERM U631 (CIML, Marseille) / Marc DALOD et Bernard MALISSEN
Laboratoire d'Immunologie des Tumeurs, Centre de Recherche en Cancérologie de Marseille (Marseille) / Daniel OLIVE
INRA (Jouy en Josas) / Nicolas BERTHO et Isabelle SWARTZ-CORNIL
Institut de Biologie Structurale (Grenoble) / Franck FIESCHI
Institut de Génétique Moléculaire de Montpellier (Montpellier) / Marc PIECHAZYCK
Société BASF (Lyon) / Valérie ANDRE et Nicolas BECHETOILLE
Groupe Hospitalier Pitié Salpêtrière (Paris) / Dr Jean-Baptiste BACHET
Groupe Hospitalier Universitaire Ambroise Paré (Paris) / Pr Jean-François EMILE
Hôpital de la TIMONE / Dr Sébastien SALAS
Institut Bergonié (Bordeaux) / Pr Jean Michel COINDRE, Dr Isabelle HOSTIEN, Dr Frederic CHIBON
ImmunID Technologies (Grenoble) / N. PASQUAL
Université d’Auvergne/CHU (Clermont Ferrand) / Marc BERGER
INSERM U1035 (Bordeaux) / Jean-Max PASQUET
CNRS 8619-IBBMC (Orsay) / Michel LEPOIVRE
USR3010 – LJC CNRS (Lyon) Equipe Mechano-genetics of the cell / Françoise ARGOUL
Faculté de medicine, U895 (Nice) Cell death differentiation and cancer / Dr Patrick AUBERGER

Principales collaborations internationales
Société ROCHE (Penzberg, Allemagne) Carola RIES
Société GlaxoSmithKline (Brentford, UK/Agnes Goetschel)
Brad NELSON (Victoria British Columbia, Canada)
PHARMAMAR (Carlos GALMARINI, colmenar viejo, espagne)
Renji Hospital Stem cell research, (Shanghai, China) / Pr. Wei-Qiang GAO
Institute of Biomaterials and Biomedical engineering (University of Toronto, Canada) / Peter ZANDSTRA

Réseaux Nationaux et Internationaux
GSF-GETO
EUROSARC (18 centres dans 8 pays)
World Sarcoma Network ( 13 pays)

CENTRE DE RECHERCHE EN CANCEROLOGIE DE LYON (CRCL)
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